Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract.

Sojeong Jin,Min-Koo Choi,Sowon Lee,Hyuna Kim,Im-Sook Song,Ji-Hyeon Jeon

doi:10.3390/pharmaceutics11040189

Sojeong Jin, Min-Koo Choi + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics11040189

Copy DOI

Journal: Pharmaceutics	Publication Date: Apr 18, 2019
Citations: 21	License type: CC BY 4.0

Affiliation: Dankook University, Kyungpook National University

Abstract

We aimed to assess the potential herb–drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC50 value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb–drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.

Highlights

Diabetes mellitus is a major health-threatening disease because the number of newly diagnosed diabetic patients is sharply increasing worldwide [1]
Considering that intravenous metformin was not affected by the multiple treatment of red ginseng extract (RGE), the increased metformin concentrations and urinary excretion following its oral administration could be explained from the increased absorption of metformin, which is consistent with the increased absorptive permeability of metformin and the increased intestinal Oct1 expression by the repeated RGE treatment (Figures 2–4). In this pharmacokinetic herb–drug interaction study, a single dose of RGE was administered to investigate whether RGE treatment could directly affect the ADME or PK properties of metformin through the inhibition of critical pathways, such as OCT and MATE
Multiple administration of RGE was performed to investigate whether RGE treatment could regulate the expression of drug transporters (Oct1, Oct2, Mate1, and plasma membrane monoamine transporter (Pmat)) that affect the ADME or PK properties of metformin

Summary

Introduction

Diabetes mellitus is a major health-threatening disease because the number of newly diagnosed diabetic patients is sharply increasing worldwide [1]. The duration and level of hyperglycemia in type 2 diabetic patients are highly associated with the risk of diabetic complications [2]. Achieving glycemic control in the early stages of therapy is very important for diabetic complications in type 2 diabetes mellitus. Using add-on therapy with other drugs that have a different mode of action alongside metformin has been recommend and metformin is the most prescribed anti-diabetic, as either mono or combination therapy with other drugs in type 2 diabetic patients [3]. Metformin is extensively eliminated via renal route as a parent form, in which renal tubular secretion mediated by cationic transporters is involved [4]. In the metformin absorption process, cationic transporters were involved. In the dose-dependent process, OCT1/Oct, MATE1/Mate, and plasma membrane monoamine transporter (PMAT in humans; Pmat in rats) are involved in a coordinated manner [10]

Objectives

Methods

Results

Conclusion